| Isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), precursors for the biosynthesis of terpenoids, can be formed either by the mevalonate or methylerythritol phosphate pathway. The methylerythritol phosphate (MEP) pathway is not present in humans, therefore the enzymes of the pathway are potential targets for the development of novel antibiotic agents. Five steps, catalyzed by the ispD-H proteins, are required for the enzymatic conversion of MEP to IPP and DMAPP. Analogues for MEP, aminomethylerythritol phosphate (NMEP), methylerythritol thiophosphate (MESP), and thiomethylerythritol phosphate (SMEP) were synthesized and their enzymatic activity for conversion to the cyclic intermediates by the consecutive action of three proteins, ispD, ispE, and ispF, is examined. The last step of the pathway, catalyzed by the ispH, requires elimination of the hydroxyl group from hydroxydimethylallyl diphosphate (HDMAPP), the immediate precursor of IPP and DMAPP. Analogues of HDMAPP, aminodimethylallyl diphosphate (NDMAPP), and thiodimethylallyl diphosphate (SDMAPP) were synthesized as substrates or inhibitors for ispH protein. |
